Inflammatory bowel disease (IBD), including Crohn's disease (CD) and UC affects approximately 1.5 million Europeans, and its peak onset is in persons with 15 to 30 years of age. IBD incidence is still increasing in developing countries. In France, 64,399 UC patients were estimated from 2008 health security agency records. UC involves the rectum and may affect part of the colon or the entire colon (pancolitis) in an uninterrupted pattern. Changes in diet, antibiotic use, environmental risk factors, and intestinal microflora are involved in IBD pathogenesis and have contributed to the increased prevalence of IBD during the past century.
Despite tremendous advances in our understanding of the pathobiology of IBD, current treatments are not efficient to control the disease over the long term. Indeed, 15-25% of patients with UC are still operated on (total colectomy) and the most powerful treatments (anti-TNF antibodies) provide complete remission at one year of treatment in only 30% of the patients enrolled in clinical trials. Moreover, UC increases the risk of colorectal cancer (18% at 30 years). Recently, the estimated annual per-patient direct medical costs of UC ranged from $6217 to $11 477 in the USA and from 8949 to 10 395 in Europe. Hospitalizations accounted for 41-55% of direct medical costs. The indirect costs accounted for approximately one-third of total costs in the United States and 54-68% in Europe. The total economic burden of UC was estimated at $8.1-14.9 billion annually in the USA and at 12.5-29.1 billion in Europe. Total direct costs were $3.4-8.6 billion in the USA and 5.4-12.6 billion in Europe. Direct costs, hospitalizations and surgeries increased with worsening disease severity. UC is a costly disease and hospitalizations contribute significantly to direct medical costs, and indirect costs are considerable. A better medical control of the disease is required. So far, current treatments are empirically used in UC. They mainly target the immune system and inflammation (aminosalicylates, steroids, and immunomodulators), while new treatments targeting epithelial abnormalities (i.e. ER stress, oxidative stress) will probably be more effective (and better tolerated), to maintain a prolonged remission or even to cure UC. Thus, drugs that prevent primary epithelial defects are mandatory to better manage UC, improve patient's quality of life, avoid terminal complications and considerably reduce the costs of care of UC.
Orexins (orexin-A and orexin-B) are hypothalamic peptides involved in the sleep/wake control which interact with two class A GPCR sub-types, OX1R and OX2R. Activation of these receptors by orexins classically induced cellular calcium transients through Gq-dependant and -independent pathways. It was recently demonstrated that OX1R was highly ectopically expressed in digestive cancer cell lines derived from colon, pancreas and liver cancers in which orexins: 1) induce a strong mitochondrial apoptosis; 2) induce a strong inhibition of tumor growth in nude mice xenografted with cancer cells. These effects were mediated by an original mechanism involving: i) the presence of two ITIM (immunoreceptor tyrosine inhibitory motif) sequences in OX1R which are tyrosine phosphorylated in the presence of orexins; ii) the recruitment and activation of the tyrosine phosphatase SHP-2 which is responsible for mitochondrial apoptosis involving cytochrome c release from mitochondria to cytosol and caspase-3 and caspase-7 activation. However the involvement of orexins in the treatment of IBD has never been investigated.